Organic acid addition salt of alkanol-substituted s-triazines

ABSTRACT

NOVEL ALKANOL SUBSTITUTED S-TRIAZINES OF THE FORMULA   2-(HO-C(-R1)(-R2)-),4-(Y-),6-(Z-)-S-TRIAZINE   WHEREIN R1 AND R2 CAN BE THE SAME OR DIFFERENT AND ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF 1-6 CARBON ATOMS AND HYDROXY ALKYL OF 1-6 CARBON ATOMS; Y IS SELECTED FROM THE GROUP CONSISTING OF-CH3, -CH2HAL, -CHHAL2, HAL, -OR, SR AND   -N(-R3)-R4   WHEREIN HAL IS A HALOGEN ATOM, PREFERABLY CHLORINE, R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF 1-6 CARBON ATOMS AND ALKYL OF 1-6 CARBON ATOMS SUBSTITUTED BY -OH, -OR5, -NHR5, -N(R6)2 OR A HALOGEN ATOM, R3 AND R4 AND HAVE THE SAME SIGNIFICANCE AS R1 AND R2 AND FURTHERMORE MAY BE CLOSED TO A RING, POSSIBLY WITH THE INCLUSION OF A FURTHER HETEROATOM, SUCH AS A PIPERAZINE, PEPERIDINE, PHENOXAZINE, 9,10-DIHYDROPHENAZINE OR PREFERABLY MORPHOLINE RING AND R5 IS SELECTED FROM THE GROUP CONSISTING OF ARYL SUCH AS PHENYL AND ALKYL OF 1-6 CARBON ATOMS, R6 TAKEN INDIVIDUALLY ARE ARYL OR ALKYL OF 1 TO 6 CARBON ATOMS AND TAKEN TOGETHER CAN BE CLOSED TO A RING WITH THE NITROGEN ATOM, POSSIBLY WITH INCLUSION OF A FURTHER HETEROATOM, AS DESCRIBED ABOVE WITH REFERENCE TO R3 AND R4, AND Z IS   -N(-R3)-R4   WHEREIN R3 AND R4 HAVE THE SAME SIGNIFICANCE AS ABOVE, Y PREFERABLY BEING -CH3, -CH2CL, -CHCI2 OR PARTICULARLY -CCL3 OR ALSO Z, AS WELL AS THEIR PHARMACOLOG ICALLY ACCEPTABLE ACID ADDITION SALTS. THE COMPOUNDS POSSESS BIOLOGICAL ACTIVITY SUCH AS AN ANALGESIC ACTIVITY AND ESPECIALLY AN ANTIPHLOGISTIC OR ANTIINFLAMMATORY ACTIVITY.

United S ate 3,583,986 ORGANIC ACID ADDITION SALT OF ALKANOL- SUBSTITUTED S-TRIAZINES Werner Heimberger, Hanan am'Main, Germany, assignor 'to Deutsche Goldund Silber-Scheideansta'lt vormals Roessler, Frankfurt am Main, Germany No Drawing. Continuation-impart of application SerrNo. 594,647,'Oct. 31, 1966. This application Feb. 9, 1968, :-,Ser.No.'704,237 Y Claims priority, applicatiosri fiesrmany, Feb. 17,- 1967,

' Int. Cl. C0711 sis/18,5500 U.s. Cl. 260249.9 v. 3 Claims ABSTRACT OF THE DISCLOSURE Novel alkanol substituted s-triazines of the formula R4 .l wherein Hal is a halogen atom, preferably chlorine, R is selected from the group'consisting of hydrogen, alkyl of 1-6 carbon atoms and ,alkyl of 16 carbon atoms substituted by OH, OR -T-NHR -N (RQ or a'halo-I gen atom, R and R and have the same significance as R and R and 'furthermore may be; closed toa ring, possibly with the inclusion of a further heteroatom, such as 21 piperazine, piperidine, phenoxazine,; 9-,l0-dihydro-' phenazine or preferably morpholine ring and R Iis' selected from the group consisting of aryl such as phenyl and alkyl of 1-6 carbon atoms, R taken individually. are aryl or alkyl of 1 to 6 carbon atoms and taken together can be closed to a ring with the nitrogen atom, possibly with inclusion of a further heteroatom, as described above with reference to R and R and is RELATED APPLICATION This application is a continuation-in-part of applica tion Ser. No. 594,647, filed Oct. 31, 1966. 111

3,583,986 Patented June 8, 197.1

ice

GENERAL DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTS I THEREOF t "The-new compounds according to the invention described above canbe prepared by saponifying compounds of the formula Y 5 analgesic and anti-inflammatory activity can be prepared wherein R is alkyl or hydroxy alkyl of 16 carbon atoms or aryl or hydroxy aryl, in the presence of a Water miscible organic solvent, especially a lower alkanol, and preferably methanol, and in the presence of about molar quantities of barium hydroxide or sodium hydroxide, potassium hydroxide at a temperature between 0 C. and the boiling point of the solvent, preferably between about and C. to form a compound of Formula I. In the event that Y initially represents the group -CHa1 the compound can be reacted with an amine of the formula wherein R and R have the same significance as above to form compounds wherein Y is in quantities of 0.1 to about 10 wt. percent at room or raised temperatures. In order to facilitate the reaction it is expedient to use a lower alkanol as solventJIt, how-' ever, also is possible to uses. sufiicient quantity of the amine I v that the starting triazine dissolves therein. The ratios of the compounds used, for example, can be between 1 25 and 1:10. If the amine is a solid substance, it can first be dissolved in a small quantity of an organic solvent, such as,.for example, acetone, ethyl acetate, dioxane or alkanols. If desired, the reaction can also be carried out in the presence of catalytic quantities of water or alkali metal hydroxide. The reaction can be carried out at room The salts of the compounds which also possess a strong with the'acidscommonly used in making pharmacologically .acceptable. salts, such...as,...-for .example, -.sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, benzyl sulfonic, p-toluene sulfonic, camphor sulfonic, methane sulfonic, quazulonic sulfonic, maleic, fumaric, succinic, tartaric, lactic, citric, ascorbic, glycolic, salicylic and the like acids.

The compounds according to the invention and their salts, for example, provide a strong anti-inflammatory action or antiphlogistic action on carrageen edema of the the/ v 'The'following table indicates the arrest" in carrageen edema of the rats paw upon oral administration of 30 mg./kg. of several illustrative compounds according to the invention (results in percent of edema arrest as compared to control group) and the acute toxicity of such compounds. The antiphlogistic action investigations were carried out according to the method of Domenjoz and Coll., Arch. Exp. Pharm. Path. 230, 325 (1957), and the acute toxicity tests were "carried out according to the method of Miller and Tainter, Proc. Soc. Exper. Biol. and Med. 57, 261 (1944) with a' 24hour observation period.

TABLE Arrest in carrageen edema at 30 mg./kg. LD

dosage, oral rug/kg. (rat) percent (rat) oral 57 ca. 2,000 50 ca. 1,000 5?. ca. 1,000

D 9220:2-trichloromethyl-4-(l-methyl 1 hydroxyl)- ethyl-6-morpholino-s-triazine D 9721=2-ethylamino-4-(l-methyl-l-hydroxyl)-ethyl 6- piperazino-s-triazine D 9722-:2-ethylamino-4-(1-methyl-1-hydroxy)-ethyl 6- piperazino-hydrochlorides-s-triazine The compounds according to the invention have good anti-infiammatory-activity and the indications as anti-inflammatory agents are as follows:

periarthritis) The novel compounds according to the invention can be used, if desired, also in combination with other medicaments, in the form of pharmaceutical compositions suited for enteral and parenteral application.

The enteral administration can, for instance,.be effected in the form of tablets, capsules, pills, drages, suppositories, oily and aqueous solutions or suspensions and emulsions..The parenteral administration can be effected in the form of injectable oily and aqueoussolutions or suspensions and emulsions.

rats paw upon oral administration in dosages of 10 -100 The dosage depending upon form of administration can be between 0.1 and 500 mg. one or more times a day.

Tliefollowing examples will serve to illustrate the coin- .pounds.according to.the invention. 1

EXAMPLE 1 50 g. of 2-trichloromethyl-4-morpholino-6-[a (carbethoxy)-a-methyl-u-oxyethyl] -s-triazine were dissolved in 300 ml. of methanol and the solution heated to boiling. 42 g. of Ba(OH) -8H O were dissolved in 400 m1. of hot methanol and such solution added to the triazine solution over a 3 hour period while the latter was constantly boiled. The triazine solution which initially was clear became cloudy as the saponification proceeded upon addition of the l3 a(,O H) solution. The reaction mixture was then boiled down without first separating the solids and the residue stirred up-with dilute HCl whereupon CO was set free, The water insoluble portion was taken up in methylene chloride. After such solution had been washed neutral it was boiled down without first separating the solids and theresidue stirred up withdilute' HCl whereupon CO was set free. The water insoluble portion was taken up in methylene chloride. After such solution had been washed EXAMPLE 2 a 85 g. of 2-trich1oromethyl-4-ethylamino-6-[a (carbethoxy)-u-methyl-oxyethyl]-s-triazine were dissolved in 300 ml. of methanol and heated to boiling.

72 g. of Ba(OH) were dissolved in 400 m1. of hot methanol and the non-dissolved BaCO filtered off. This solution was then added to the boiling triazine solution over a 3 hour period. The processing thereafter was as in Example 1.51 g. or ayield 75% of theory was obtained as the crystalline residue. When recrystallized from ligroin the 2-trichloromethyl-4-ethylamino-6-a-methyl-a-hydroxyethyl-s-triazine of a M.P. of -82 C. was obtained.

EXAMPLE 3 g. of a-(carbethoxy)--methyl-u-oxyethyl-4-ethanolamino-6-trichloromethyl-s-triazine were dissolved in ml. of methanol. Then a solution of 93 g. of

114 g. of w(carbomethoxy-a-methyl)-a-oxyethyl 4- morpholino-6-trichloromethyl-s-triazine (M.P. 9095 C.) were dissolved in 500 ml. of methanol and a solution of 90 g. of Ba(OH) 8H O in 750 ml. of methanol added thereto over a 30 minute period. The mixture was then refluxed for 1 /2 hours. The processing was as described in Example 3.

'Yield: 51 g. of 2-(c-hydroxy)-ethyl-a-methyl-4mor pholino- 6-t richloromethyl-s-triazine.

EXAMPLE 5 Analogously the following compounds:

(a) 2-(a-hydroxy-u-methyl)-ethyl-4-(3 methoxypropyl)- amino-6-trichloromethyl-s-triazine (M.P. 41-43 C.) (b) 2-(a-hydroxy-a-methyl-ethyl)-4-piperidino 6 trichloromethyl-s-triazine (M.P. 82 -87 C.) (c) 2-(a-hydroxy-u-methyl-ethyl)-4-(2 hydroxypropyl)- amino-6-trichloromethyl-s triazine (syrup) EXAMPLE 6 77.5 g. of 2-a-cargomethoxy-a-methyl-a-oxyethyl-4-(3- hydroxy)-propylarnino-6-trichloromethyl-s-triazine were heated with 145 ml. of thionyl chloride to produce 2-05- carbomethoxy-a-methyl-u-oxyethyl-6-trichloromethyl striazine, which was not isolated, but processed in the usual manner as a crudeproduct, which was dissolved in 100 ml. of methanol and heated under reflux for 90 minutes with 63 g. of Ba(OH) -8H O dissolved in 530 ml. of methanol. After processing as described above, 34 g. or

54.%...of..theory...of.2-a:hydroxyx-methyl1ethyl-4...- (3)-.

chloropropylamino-6-trichloromethyl5s-triazine of a M.I 9 of '68-7 1 C. were obtained. EXAMPLE 7 41.25 g. of a-carbethoxy-a-methyl-a-oxyethyl-4-piperazino-6-trichloromethyl-s-triazine (0.1 mol) were heated to reflux with 161.6 g: (1.8 mol) 50% aqueous ethylamine for 4 hours.

The reaction solution was then concentratedunder vacuum and the residue dissolved in 200 ml. of methylene chloride. The solution was washed with water to extract the residue of ethylamine. Then the solution was concentrated under vacuum.;Thefresidue yielded 22.3 g. of 2- (a-carboxy-a-methyl)-oxyethyl 4 piperazino 6 ethylamino-s-triazine which was 66% of theory.

EXAMPLE 8 33.8 g. of Z-a-carbethoxy-u-methyl-a-oxyethyl-4-piperazino-6-ethylamino-s-triazine (0.1 mol) were dissolved in 500 ml. of methanol and their a solution of 10 g. of sodium f hydroxide in 50 ml. of water was added. After keeping at room temperature for two days the solid Na CO formed was separated and the solution concentrated under vacuum. The residue was dissolved with 200 ml. of ethyl acetate and after Washing. with water the solution was' boiled down. H The residue yielded 20.75 g. of 2-u-methyl-u-hydroxyethyl-4-piperazino-6 ethylamino-s-triazine which was 78% of theory. Its melting point was 88-.92 C.

EXAMPLE 9 ethylamino-s-triazine (0.1 mol) were dissolved in 200 ml. of ethyl acetate and 3.65 g. of gaseous HCl (0.1 mol) F were introduced. The formed solids of hydrogen chloride of the triazine compound were separated and washed with ethyl acetate and thereafter dried.

The yield of 2-a-hydroxyethyl-a-methyl-4-piperazino-6- ethylamino-s-triazine-hydrogen chloride was 25.6 g. or 84.6% of theory. Its melting point under decomposition was 281-285 C. x

EXAMPLE 10 (a) 36.2 g. of 2-(a carbethoxy-a-methoxy)-0xyethyl-4- N-methyl-piperazino 6 ethylamino-s-triazine (0.1 mol, 5 viscous, produced after Example 7 from 2-(u-carbethoxya-methyl)-oxyethyl-4-N'-methyl-piperazino 6 trichloromethyl-s-triazi'ne, melting point 95-98 C.) were dissolved in 500 ml. of methanol and refluxed with 31.5 g. of. Ba(0H) -8H O (0.1 mol) for two hours. After cooling down 7.3 g. of gaseous HCl (0.2mol') were added whereupon CO was ,set free. The solution was concentrated. and the residue heated with 200 ml. of ethanol for two hours whereupon the saponified triazine compound was dissolved. The solid BaCl was separated and the solution concentrated under vacuum. The residue was washed with Water and dried.

The yield of 2-a-hydroxyethyl-a-methyl-4N-methylpiperazino--ethylamino-s-triazine was 20.1 g. or 71.8% of theory. Its melting point was 95-99" C.

(b) 28 g. (0.1 mol) of the compound prepared as above under (a) were dissolved in 150 ml. of methanol and added to a solution of 11.6 g. (0.1 mol) of maleic acid in 150 ml. of methanol.

The solution was allowed to stand overnight at room temperature, whereby the maleic acid addition salt crystallized out. It was filtered off, washed with a small quantity of cold methanol. The mother liquor was concentrated to one-half its volume and upon cooling a further quantity 15 of the salt crystallized out. After filtering ofiF, washing and drying, a total of 29.7 g. of Z-a-hydroxyethyI-a-methyl- 4-N'-methylpiperazino-6-ethylamino-s-triazine maleate of a melting point of 121124 C. were obtained. The yield was 75.2% of theory. 7

EXAMPLE 11 (a) 34.2 g. (0.1 mol) of 2-trichloromethyl-4-(a-acetoxy-a-methyD-ethyl 6 ethylamino-s-triazine were introduced into a solution of 9.2 g. (0.4 mol) of Na in 200 ml. of methanol and the mixture heated under reflux for 2 hours. After cooling down the pH of the solution was adjusted to 6 with aqueous HCl and the methanol dis- --tilled off under vacuum. The crystalline residue was washed with water and dried. 19 g. of 2-methoxy-4-(w methyl a hydroxy)-ethyl 6 ethylamino-s-triazine of a melting point of 5 861 C. were obtained. The yield was 75% of theory.

(b) 40.0 g. (0.1 mol) of 2-trichloromethyl-4-(amethoxy-carbonyloxy-u-methyl)-ethy1 6-N'-morpholinos-triazine were reacted in an analogous manner to obtain 18.4 g. of 2-methoxy-4- (a-methyl-a-hydroxy)-ethyl-6- morpholino-s-triazine of a melting point of 132-134 C The yield was 72.5% of theory.

(c) 41.2 g. (0.1 mol) of 2-trichloromethyl-4-(umethoxy-carbonyloxy a methyl) ethyl 6 N'-methylpiperazino-s-triazine were reacted in an analogous manner. However, when the methanol was distilled off a syrupy residue was obtained which was taken up in methylene chloride and washed with water. The methylene chloride was. then distilled oil? and the residue extracted with hexane whereby the impurities were left in the residue. When the hexane solution was boiled down a syrupy residue remained Which crystallized upon standing. 16 g. of 2-methoxy-4-(a-methyl-a-hydroxy)-ethyl 6 N'-methyl-piperazino-s-triazine with a melting point of 57-63 C.

V I 1 I H V wereobtained. The yield was 60% of theory.

26.6 g. of 2-a-hydroxyethyl-a-methy1-4-piperazino-6 EXAMPLE 12 35.8 g. (0.1 mol) of 2-trich1oromethyl-4-(a-methoxycarbonyl-u-methyl) ethyl 6 ethylamino-s-tn'azine were heated under reflux in a mixture of ml. of methanol and ml. of 2 N NaOH for 3 hours. After cooling the 7 pH of the mixture was adjusted to 3 with conc. HCl.

After standing overnight the crystalline product was filtered off, washed and dried. 15.5 g. of 2-hydroXy-4-(amethyl-a-hydroxy)-ethyl-6-ethylamino-s-triazine of a melting point of 235-238 C. were obtained. The yield was 78.3% of theory.

EXAMPLE 13 40.0 g. 0.1 mol) of 2-trichloromethyl-4-(u-methoxycarbonyloxy a methyl)-ethyl 6 morpholino-s-triazine were introduced portionwise into a solution of 9.2 g. (0.4

distilled off under vacuum and the residue taken up in methylene chloride and washed with water. After boiling down a syrupy residue was obtained which crystallized on standing. The crystalline mass was stirred up with a little hexane and after drying 18.5 g. of 2eisopropoxy-4-(amethyl-u-hydroxy) ethyl 6 morpholino-s-triazine of a melting point of 55-59 C. were obtained. The yield was 65.6% of theory.

of Z-B-aminoethoxy 4 -1'(a-rnethylrqt-hydroxy.)-ethyl=6 morpholino-s-triazine of a melting point of 131-137" C.

were obtained. The yield was 60% of theory. '5 i The following table gives the formulae "ofthe starting EXAMPLE 14 v 5 materials and products of the examplesj F or sake of sim- 40.0 g. (0.1 mol) of 2-trichloromethyl-4-(u-methoxyii i Y, i V carbonyloxy oz methyl)-ethyl 6 morpholino-s-triazine 4 i were added portionwise into a solution of 9.2 g. (0.4 mol) of Na in 150 ml. of ethanol amine at 50 C. and then stirred for a further 30 minutes at this temperature. Th 10 N- excess ethanol amine was distilled off under vacuum and 1 a the residue taken up in methylene chloride and washed W111berepresentedtherembythesymbol with water. The reaction product was then extracted from i the methylene chloride solution with 50 m1. of 2 N acetic acid and the extract adjusted to a pH of 10 with NaOH 15 whereby the triazine compound crystallized out. 17 g.

Example Starting material End product r 1 00 0 C OHQPOH C(CHahOJiOCzH; 'fm c-Q 2 ccrnococn can" 011 t f az ifjztr c130- NHCQH; HCzH, 3 o Ha)2 2Ha i i -'7Q( Ha)2 H 01 cc1 o-- L.

NHCHz-CHzOH I NH0H2-CH0H 1 4 ommaooocn i '0 on on -1 19 i T "om- L i m (i I; i- H h ewnmocoom V nonmeta- 5a onoonc- NHCHPCHFCH2O CH3 NHiHr' HT- HT- IA owmno o'on, owmnon 5b c130- onek 1 I i H H I.

imm f cm f rrmoa a 5c... 013cc130- ,7 i i v I I NHCHz-CH(OH)CH: NHCHz- CH(OH)CH: ([KCHahGfi-OCH; w (|'J(CH3)2OH 1 O 6 G1 C- l 1 NHCHz-CHnCHzOH Nanny-currents; 7 Q L B C GH QQ C C130- HOgHN-QL TABLE-Continues Example 7 Starting material @End product 8 ownnzoooo zizn ""o oH3 ioH HsC2HN-Q I HsCzHN- t,, t 9 C(CHMOH C(CHmOH v z .v nfiolnrwq m an-Q v 16 H NH- 16 H Nrrnoi 10a C(CHahOCOCzHg, ownmoH ll mmrm- H CzHN-| if H Nom 16 H N-CHQ 11a C(CH3)2-0CCH3 C(CHQgOH II 013C- CH- l NHCzHa NHCzHg 11b /C(CHa)2O%| OCHa C(CH3)20H 0 CI3C onao- N H o N H b 11c C(CHahOCCCHa (CH3)2OH ll ClaC- 4 CH3O I N H N-OH: N H N-CHa 12 ownmoooorn C(CHaMOH NHC2H5 NHCzHg 13 ownmoooom C(CHmOH ll 113 ono-fi H- l70 CH N H 0 3 rf H 0 U 14 C(CHahOCOCHaI C(CHhOH n cnol HZNCHZCH2O if H o N H o Iclaim:

1. An acid addition salt between a pharmaceutically is selected from the group consisting of CH CH Hal,

acceptable organic acid and an alkanol-substituted s-triazine of the formula CHHal CHa1 Ha1, OR, SR and wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 to 6 carbon atoms and lower alkyl of 1 to 6 carbon atoms substituted with a substituent selected from the group consisting of --OH, -OR

atoms and lower hydroxy alkyl of 1 to 6 carbon atoms, Y --NHR N(R and Hal, Hal signifies a halogen atom, R and R have the same meaning as R and may be the same or difierent with the proviso that only oneflofw these two radicals shall be said snbstittltedalkyl andwherein R and R together may form piperazino, N-methylpiperazino or piperidino, R is selected fromthegroup consisting of phenyl and lower alkyl of 1 to 6 carbon atoms, R is selected from the group consisting of phenyl I and lower alkyl of 1 to 6 carbon atoms, and Z vis selected from the group consisting of wherein R and R have the same significance as above.

12 2. The maleate of an alkanol-substituted s-triazine as defined'in claim 1. r

azino-6 ethylamino-s-triazine maleate.

JOHN M. FORD, Primary Examiner us. 01, X.R'. 

